ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1164del (p.His388fs)

dbSNP: rs1554298082
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570757 SCV000663496 pathogenic Hereditary cancer-predisposing syndrome 2022-03-02 criteria provided, single submitter clinical testing The c.1164delT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1164, causing a translational frameshift with a predicted alternate stop codon (p.H388Qfs*10). This pathogenic mutation has been reported in a homozygous state in two siblings with constitutive mismatch repair deficiency (CMMR-D) syndrome; both parents were heterozygous for this mutation however their clinical histories were not provided (Chmara M et al. Genes Chromosomes Cancer 2013 Jul; 52(7):656-64). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV000570757 SCV000691001 pathogenic Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587567 SCV000697281 pathogenic Mismatch repair cancer syndrome 1 2016-08-16 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1164delT (p.His388Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate C-terminal MutL dimerisation domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1831dupA/p.Ile611fs). This variant has been reported in two siblings with constitutive mismatch repair deficiency in homozygous state, their parents being heterozygous carriers for the variant. The variant is absent in 115240 control chromosomes from ExAC. Taken together, this variant is classified as Pathogenic.
Sema4, Sema4 RCV000570757 SCV002529761 pathogenic Hereditary cancer-predisposing syndrome 2021-03-02 criteria provided, single submitter curation
Invitae RCV002526794 SCV003440125 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-11-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480324). This premature translational stop signal has been observed in individual(s) with autosomal recessive PMS2-related conditions (PMID: 23629955). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His388Glnfs*10) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
Myriad Genetics, Inc. RCV003451228 SCV004188573 pathogenic Lynch syndrome 4 2023-09-20 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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